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|Title:||Cancer Cell-Derived Clusterin Modulates the Phosphatidylinositol 3'-Kinase-Akt Pathway through Attenuation of Insulin-Like Growth Factor 1 during Serum Deprivation|
|Authors:||Jo, Hakryul;Jia, Yonghui;Subramanian, Kulandayan K.;Hattori, Hidenori;Luo, Hongbo|
|Publisher:||American Society for Microbiology|
|Description:||Cancer cells in their respective microenvironments must endure various growth-constraining stresses. Under these conditions, the cancer cell-derived factors are thought to modulate the signaling pathways between cell growth and dormancy. Here, we describe a cancer cell-derived regulatory system that modulates the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway under serum deprivation stress. Through the use of biochemical purification, we reveal that cancer cell-secreted insulin-like growth factor 1 (IGF-1) and clusterin, an extracellular stress protein, constitute this regulatory system. We show that secreted clusterin associates with IGF-1 and inhibits its binding to the IGF-1 receptor and hence negatively regulates the PI3K-Akt pathway during serum deprivation. This inhibitory function of clusterin appears to prefer IGF-1, as it fails to exert any effects on epidermal growth factor signaling. We demonstrate furthermore that the constitutive activation of oncogenic signaling downstream of IGF-1 confers insensitivity to the inhibitory effects of clusterin. Thus, the interplay between cancer cell-derived clusterin and IGF-1 may dictate the outcome of cell growth and dormancy during tumorigenic progression.|
|Standard no:||Jo, Hakryul, Yonghui Jia, Kulandayan K. Subramanian, Hidenori Hattori, and Hongbo R. Luo. 2008. “Cancer Cell-Derived Clusterin Modulates the Phosphatidylinositol 3'-Kinase-Akt Pathway through Attenuation of Insulin-Like Growth Factor 1 during Serum Deprivation.” Molecular and Cellular Biology 28 (13) (May 5): 4285–4299. doi:10.1128/mcb.01240-07. http://dx.doi.org/10.1128/MCB.01240-07.|
|Appears in Collections:||HMS Scholarly Articles|
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